期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 19, 页码 15886-15895出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.325142
关键词
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资金
- National Institutes of Health [R01-DK044498, R01-Hl049879]
- Ohio Agricultural Research and Development Center
beta-Carotene is the major dietary source of provitamin A. Central cleavage of beta-carotene catalyzed by beta-carotene oxygenase 1 yields two molecules of retinaldehyde. Subsequent oxidation produces all-trans-retinoic acid (ATRA), which functions as a ligand for a family of nuclear transcription factors, the retinoic acid receptors (RARs). Eccentric cleavage of beta-carotene at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are beta-apocarotenals and beta-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the beta-apocarotenoids significantly activated RARs. Importantly, however, beta-apo-14'-carotenal, beta-apo-14'-carotenoic acid, and beta-apo-13-carotenone antagonized ATRA-induced transactivation of RARs. Competitive radioligand binding assays demonstrated that these putative RAR antagonists compete directly with retinoic acid for high affinity binding to purified receptors. Molecular modeling studies confirmed that beta-apo-13-carotenone can interact directly with the ligand binding site of the retinoid receptors. beta-Apo-13-carotenone and the beta-apo-14'-carotenoids inhibited ATRA-induced expression of retinoid responsive genes in Hep G2 cells. Finally, we developed an LC/MS method and found 3-5 nM beta-apo-13-carotenone was present in human plasma. These findings suggest that beta-apocarotenoids function as naturally occurring retinoid antagonists. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary beta-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer.
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